Today is the third day of the American Society of Hematology (ASH) 2012 annual meeting in Atlanta, and it is packed full with multiple myeloma-related presentations. Presentations started early in the morning and will con­tinue through the afternoon.

Over the course of today, at least 11 different oral sessions, many of which are being held simultaneously, will include presentations about myeloma-related topics.  The Beacon will summarize presentations from the four most relevant sessions in updates such as this one.  This update, in particular, covers presentations from the first of those four oral sessions.

BHQ880

Dr. Nikhil Munshi from the Dana-Farber Cancer Institute in Boston gave the first talk of the session. He presented results from a Phase 2 study of BHQ880 in smol­der­ing multiple myeloma patients at risk of progressing to symp­tomatic multiple myeloma (abstract ^[1]).

BHQ880 is an anti­body that targets DKK-1, a protein that inhibits bone formation and is overabundant in people with multiple myeloma.  BHQ880 therefore helps to restore bone formation.  Several ongoing Phase 2 studies are investigating the effect BHQ880, alone or in com­bi­na­tion with Zometa ^[2] (zoledronic acid), has on myeloma bone disease.

The current study included 39 intermediate- and high-risk smol­der­ing multiple myeloma patients with a median age of 61 years.

Among the 15 patients followed during at least six months of treat­ment with BHQ880, 60 per­cent experienced increased bone strength according to quantitative computed tomography.  Patients’ bone strength increased by approx­i­mately 2 per­cent, which Dr. Munshi said is similar to that observed with other approved bone-strengthening drugs.  Dr. Munshi went on to say that it is too early to note any significant changes in bone strength via DEXA scans.

BHQ880 did not show any anti-myeloma effects.

The most common side effects included fatigue (31 per­cent), fever (21 per­cent), joint pain (18 per­cent of patients), and back pain (18 per­cent).

MLN9708

Next, Dr. Shaji Kumar from the Mayo Clinic in Rochester, Minnesota, presented updated results of a Phase 1/2 trial of MLN9708 com­bined with Revlimid ^[3] (lena­lido­mide) and dexamethasone ^[4] (Decadron) in pre­vi­ously untreated myeloma patients (abstract ^[5]; presentation slide deck ^[6] (pdf) made available by Dr.  Kumar as a courtesy to the Beacon’s readers).

MLN9708 belongs to the same class of drugs as Velcade ^[7] (bor­tez­o­mib) and Kyprolis ^[8] (car­filz­o­mib), called proteasome inhibitors. However, MLN9708 can be taken orally.

Sixty-five newly diagnosed myeloma patients with a median age of 66 years were enrolled in the study.

During Phase 1 of the trial, patients received between 1.68 mg/m² and 3.95 mg/m² of MLN9708 once weekly in com­bi­na­tion with Revlimid and dexa­meth­a­sone.  Patients participating in Phase 2 of the trial received a fixed dose of 4 mg of MLN9708 per week as part of the same com­bi­na­tion.

Among the 52 patients from Phase 2 of the study who were evaluated, the over­all response rate was 90 per­cent, with 23 per­cent achieving a complete response, 35 per­cent a very good partial response, and 32 per­cent a partial response.

Dr. Kumar esti­mated the one-year pro­gres­sion-free survival rate to be 93 per­cent.

The most common severe side effects included rash (18 per­cent), low white blood cell counts (9 per­cent), vomiting (8 per­cent), back pain (7 per­cent), low platelet counts (6 per­cent), low red blood cell counts (6 per­cent), fatigue (6 per­cent), diarrhea (6 per­cent), and electrolyte imbalance (6 per­cent).  About a third of patients developed periph­eral neu­rop­athy (pain, tingling, or loss of sensation in the extremities), and one patient died during the study.

Based on these positive results, a Phase 3 study ^[9] of the same com­bi­na­tion is cur­rently recruiting re­lapsed and refractory myeloma patients.

Kyprolis In Combination With Thalidomide And Dexamethasone

Next, Dr. Pieter Sonneveld from the Erasmus Medical Center in Rotterdam, The Netherlands, presented results from a Phase 2 study of Kyprolis in com­bi­na­tion with thalidomide ^[10] (Thalomid) and dexa­meth­a­sone (abstract ^[11]).

After four cycles of initial ther­apy with Kyprolis, thalido­mide, and dexa­meth­a­sone, patients underwent au­tol­o­gous stem cell trans­plan­ta­tion (using their own stem cells), followed by four more cycles of the Kyprolis com­bi­na­tion as consolidation ther­apy.

Dr. Sonneveld presented results from the 50 study participants who have been evaluated for response so far.  Their median age was 58 years.

Overall, 94 per­cent of patients responded to ther­apy, with 44 per­cent achieving a complete or stringent complete response, 40 per­cent a very good partial response, and 10 per­cent a partial response.

After a median follow-up of 14 months, the median pro­gres­sion-free and over­all survival times were not yet reached.

The most common side effects were gastro­in­tes­ti­nal (28 per­cent), periph­eral neu­rop­athy (21 per­cent), skin (20 per­cent), and heart-related com­pli­ca­tions (8 per­cent).

Velcade-Thalidomide Maintenance After Stem Cell Transplantation

Next, Dr. Joan Bladé from the Hospital Clinic in Barcelona, Spain, presented results from a Phase 3 trial that in­ves­ti­gated three different main­te­nance regi­mens in 266 newly diagnosed multiple myeloma patients.  Prior to main­te­nance ther­apy, the patients received one of three different initial ther­a­pies and a stem cell trans­plant (abstract ^[12]).

In particular, the Spanish researchers compared the fol­low­ing main­te­nance regi­mens: Velcade plus thalido­mide, thalido­mide alone, and interferon alpha-2b alone.

The researchers found that main­te­nance ther­apy with these regi­mens improved patients’ complete response rates by 21 per­cent, 15 per­cent, and 15 per­cent, respectively, as compared to response rates after trans­plan­ta­tion.

After a median follow-up of 35 months, the median pro­gres­sion-free survival time was significantly longer with Velcade-thalidomide than with thalido­mide or interferon alone. However, further analyses showed that only patients with low-risk chromosomal ab­nor­mal­i­ties benefited from Velcade-thalidomide as compared to thalido­mide alone.

In addi­tion, median over­all survival was not significantly different among the three treat­ment groups.

The most common severe side effects were low white blood cell counts (13 per­cent for Velcade-thalidomide, 16 per­cent for thalido­mide, and 17 per­cent for interferon) and low platelet counts (10 per­cent, 1 per­cent, and 4 per­cent, respectively).

Thalidomide Or Revlimid Treatment Followed By Velcade Treatment

Next, Dr. Charlotte Pawlyn from the Institute of Cancer Research in Sutton, United Kingdom, summarized results from a Phase 3 study that in­ves­ti­gated the use of thalido­mide- or Revlimid-based ther­apy followed by Velcade-based ther­apy for patients who did not respond to thalido­mide- or Revlimid-based ther­apy alone (abstract ^[13]).  The goal of this approach was to maximize responses and improve survival.

The study enrolled 1,736 newly diagnosed multiple myeloma patients so far.

Patients received initial treat­ment with either thalido­mide or Revlimid in com­bi­na­tion with cyclophosphamide ^[14] (Cytoxan) and dexa­meth­a­sone.

Patients who did not respond to initial ther­apy received further treat­ment with Velcade, cyclophosphamide, and dexa­meth­a­sone.

To test if the Velcade com­bi­na­tion could improve responses, patients with a minor or partial response were randomly chosen to receive either no further ther­apy or treat­ment with the Velcade com­bi­na­tion.  Patients who did not achieve at least a minor response were automatically treated with the Velcade-based ther­apy.

The researchers found that among patients who did not respond to initial treat­ment, 55 per­cent achieved an improvement in response, with 29 per­cent achieving a very good partial response or a complete response.

Among the patients who achieved a minor or partial response after their initial ther­apy with thalido­mide or Revlimid, 44 per­cent improved their responses to a very good partial response or a complete response.

Dr. Pawlyn then showed data suggesting that sequential treat­ment achieves similar very good partial response rates as compared to initial treat­ment that combines thalido­mide or Revlimid with Velcade.

The most common severe side effects were low red blood cell counts (3 per­cent to 20 per­cent), low platelet counts (11 per­cent to 14 per­cent), and low white blood cell counts (7 per­cent to 9 per­cent).

Zolinza In Combination With Revlimid, Velcade, And Dexamethasone

Last but not least, Dr. Jonathan Kaufman from the Winship Cancer Institute of Emory University in Atlanta presented results from a Phase 1 study of Zolinza ^[15] (vorinostat) in com­bi­na­tion with Revlimid, Velcade, and dexa­meth­a­sone in newly diagnosed multiple myeloma patients (abstract ^[16]; presentation slide deck ^[17] (pdf) made available by Dr.  Kaufman as a courtesy to the Beacon’s readers).

Zolinza, which is marketed by the U.S. pharma­ceu­tical com­pany Merck (NYSE: MRK), is an oral drug already approved in the United States for a certain type of lym­phoma. It also is approved for a similar use in Canada and Australia, but not in Europe.

Zolinza belongs to a class of drugs called histone deacetylase (HDAC) inhibitors, which work by increasing the pro­duc­tion of proteins that slow cell division and cause cell death. Two other drugs that have been in­ves­ti­gated as potential myeloma treat­ments – panobinostat ^[18] and Istodax ^[19] (romidep­sin) – belong to the same class of drugs.

By adding Zolinza to the highly effective treat­ment com­bi­na­tion of Revlimid, Velcade, and dexa­meth­a­sone, the researchers hoped to further improve the patients’ depth of responses.

The study included 30 newly diagnosed multiple myeloma patients with a median age of 56 years.

Patients received between 100 mg and 400 mg of oral Zolinza in com­bi­na­tion with Revlimid, Velcade, and dexa­meth­a­sone.

Overall, 97 per­cent of patients responded to ther­apy, with 30 per­cent achieving a stringent complete response, 10 per­cent a complete or near complete response, 33 per­cent a very good partial response, and 24 per­cent a partial response.

After a median follow-up of 13 months, the median pro­gres­sion-free and over­all survival were not yet reached.

The most common severe side effects were elevated liver enzymes (13 per­cent), heart-related problems (10 per­cent), low white blood cell counts (10 per­cent), blood clots (7 per­cent), periph­eral neu­rop­athy (7 per­cent), and fainting (7 per­cent).  One person died due to heart com­pli­ca­tions.

The maximum tolerated dose of Zolinza was determined to be 200 mg.

Myeloma presentations from the rest of Day 3 as well as Day 4 of the ASH 2012 meeting also will be summarized in ASH daily updates to be published at The Beacon the next few days.  Additional coverage of key research results from the meeting will con­tinue throughout the rest of the week in individual, topic-specific news articles.  For all Beacon articles related to this year’s ASH meeting, see The Beacon’s full ASH 2012 ^[20] coverage.